Persistent respiratory tract colonization of preterm infants with the genital mycoplasma species, Ureaplasma parvum and U. urealyticum, is a significant risk factor for the development of the chronic lung disorder bronchopulmonary dysplasia (BPD) (1) and may contribute to adverse pulmonary outcomes in the first year of life. There are no current effective therapies for the treatment of Ureaplasma in infected preterm infants. Our long-term objective is to develop therapies to eradicate Ureaplasma from the respiratory tract of preterm infants and prevent or ameliorate Ureaplasma-mediated lung injury. The azalide antibiotic azithromcyin (AZI) has immunomodulatory properties that make it an ideal candidate for therapy to prevent Ureaplasma-mediated lung injury in preterm infants. AZI 1) inhibits neutrophil influx and chemoattractant/cytokine release in murine lung injury models (2-4); 2) exhibits higher potency than erythromycin against clinical Ureaplasma isolates in vitro (5); and 3) is preferentially concentrated in alveolar epithelial lining fluid and macrophages (6, 7). In a neonatal murine Ureaplasma infection model, AZI, but not erythromycin treatment, improved survival and reduced lung inflammation (8). We hypothesize that AZI therapy will prevent BPD in Ureaplasma-infected preterm infants by accelerating pathogen clearance and/or down- regulating the pulmonary inflammatory response. We are currently conducting a Phase I open-label, pharmacokinetic (PK) study characterizing the single dose PK, safety, tolerability, and biologic effects of 10 mg/kg and 20 mg/kg IV AZI in mechanically ventilated 24-28 wk gestation preterm neonates who are at high- risk for Ureaplasma respiratory tract colonization and BPD. For the 10 mg/kg single dose sample, a two- compartment structural model with the clearance and volume of peripheral compartment (V2) allometrically scaled on body weight best described the PK of AZI in preterm neonates. The single dose regimen was safe, but insufficient to eradicate Ureaplasma or to suppress pulmonary inflammatory responses. Pharmacokinetic simulations indicated that even multiple dose administration of 10 mg/kg AZI would be inadequate to maintain AZI plasma concentrations above the MIC50 for Ureaplasma isolates. The specific aims of this proposal wil address the next steps preparatory to Phase III safety and efficacy trials of AZI in the preterm population. This proposal will 1) characterize the multiple-dose pharmacokinetics (PK), tolerability, safety, and biologic effects of IV AZI in mechanically ventilated preterm neonates born 24-28 weeks gestation at high risk for Ureaplasma spp. respiratory tract colonization and subsequent development of BPD; 2) conduct a multicenter, randomized, double-blind, placebo-controlled Phase IIb clinical trial to determine the safety and microbiological efficacy of a multiple dose course of intravenous AZI to eradicate respiratory tract Ureaplasma infection that might lead to physiologic BPD in preterm neonates; and 3) compare the pulmonary outcomes at 36 wk postmenstrual age and 6 months adjusted age in infants treated with AZI vs placebo. PUBLIC HEALTH RELEVANCE: Babies who are born prematurely with an infection with the bacteria Ureaplasma frequently develop a chronic lung condition caled bronchopulmonary dysplasia (BPD)(1). Currently, there are no effective therapies to treat this infection or prevent BPD in infected infants. This study will 1) evaluate the safety of and how the body processes the antibiotic azithromycin, 2) determine the effectiveness of a 3-day course of azithromycin in eliminating Ureaplasma infection from the lungs of preterm infants, and 3) compare the lung health outcomes of the infants treated with azithromycin with the outcomes of placebo-treated infants.